Wang et al. Critical Care 2014, 18:704 http://ccforum.com/content/18/6/704

LETTER

Serum miR-122 correlates with short-term mortality in sepsis patients
Huijuan Wang1,2†, Bingxiang Yu3†, Jie Deng4, Yang Jin5* and Lixin Xie1*
Sepsis is one of the leading causes of death in the ICU. The pathogenesis of sepsis remains incompletely understood, thereby impeding the development of therapeutics, diagnostics and biomarkers to predict outcomes [1]. Our previous studies have proved that miR-122, miR-193b*, miR-483-5p and miR-574-5p were all differentially expressed between sepsis survivors and non-survivors, differentiated by 28-day mortality [2,3]. However, whether these biomarkers related to patients with both sepsis and acute respiratory distress syndrome (ARDS) remains unclear. Here we evaluate the levels of these four microRNAs (miRNAs) along with C-reactive protein (CRP), procalcitonin (PCT), Sequential Organ Failure Assessment (SOFA) score, and Acute Physiology and Chronic Health Evaluation (APACHE) II score to determine the ideal biomarkers for sepsis patients. Serum samples were collected from 232 sepsis patients who were admitted to ICUs of the Chinese PLA General Hospital. All the patients met the definition of sepsis developed in 2003 [4]. Inclusion and exclusion criteria are described in Table 1. Another 24 normal individuals were also included in this study. Serum levels of miRNAs, CRP and PCT were analyzed using methods as described in detail previously [3]. This study was approved by the ethics committee of the Chinese PLA General Hospital. Appropriate informed consent was obtained from each patient and normal individual. The clinical data of these 232 patients are shown in Table 2. After comparison of the levels of the four miRNAs in three pairs of groups (normal individuals and sepsis patients, survivors and non-survivors, sepsis without ARDS and sepsis plus ARDS), only the cycle threshold of mir-122 was differentially expressed in all three (P < 0.01) (Figure 1). Univariable and multivariable regression analyses were then used to evaluate the association between miR-122 and 28-day mortality in different ICUs. After adjustment using clinical data and additional parameters (SOFA score, APACHE II score and ARDS), the odds ratio of miR-122 association with 28-day mortality was around 0.376 to 0.868 (P < 0.05) in the different ICUs. The area under the curve for the predictive value of miR-122 was around 0.706 to 0.770 (P < 0.01) with high sensitivity and specificity (Table 3). As a result, only miR-122 can be used as a biomarker with regards to patients with both sepsis and ARDS. miR-122 is a liver-specific miRNA and levels of it in serum were correlated with drug-induced liver injury [5]. We reported that miR-122 correlated with coagulation disorders in sepsis patients and serum levels of miR-122 correlated with serum antithrombin III levels [6]. Our study reveals a potential novel target to develop a biomarker for sepsis prognosis and therapeutic strategies.

* Correspondence: yjin@rics.bwh.harvard.edu; xielx@263.net † Equal contributors 5 Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA 1 Department of Respiratory Medicine, Chinese PLA General Hospital, 28th Fuxing Road, Beijing 100853, PR China Full list of author information is available at the end of the article
© 2014 Wang et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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Table 1 Inclusion and exclusion criteria
Inclusion criteria 1) Sepsis patients all met the definitions of the 2001 SCCM/ESICM/ ACCP/ATS/SIS International Sepsis Definitions Conference [4] Exclusion criteria 1) Patients who were younger than 18 years old 2) Patients who were immunosuppressed 3) Patients who did not receive adequate treatment 4) Patients who did not give their written informed consent 2) All patients received standard protocols of clinical care

Table 2 Clinical characteristics of the 232 sepsis patients
Category Demographic parameters Variables Gender (male/female) Age in years (median (range)) Clinical parameters ICU type Medical Cardiac Surgical Trauma Cancer Other APACHE II score SOFA score Acute kidney injury Mechanical ventilation Heat failure Liver failure ARDS 28-day mortality Biomarkers miR-122 miR-193b* miR-574-5p miR-483-5p CRP (mg/dl) PCT (ng/ml)
a

Sepsis (n = 232) 169/63 59 (19, 91)

232 (100%) 79 (34.05%) 95 (40.95%) 25 (10.77%) 24 (10.34%) 15 (6.46%) 18 (1, 39) 7 (0, 19) 61 (26.29%) 171 (73.71%) 121 (52.15%) 103 (44.39%) 60 (28.17%)a 45.69% 17.75 ± 3.40 cycles 17.73 ± 4.81 cycles 21.19 ± 3.64 cycles 18.99 ± 4.24 cycles 8.9 (0.1, 35) 4.63 (0.05,119.44)

ARDS data of 19 patients were missing. APACHE, Acute Physiology and Chronic Health Evaluation; ARDS, acute respiratory distress syndrome; CRP, C-reactive protein; PCT, procalcitonin; SOFA, Sequential Organ Failure Assessment. APACHE II score, SOFA score, CRP and PCT are all given as median (range). *ARDS data of 19 patients were missing.

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Figure 1 Cycle thresholds of the four microRNAs (miRNAs) in the three pairs of groups. ARDS, acute respiratory distress syndrome.

Table 3 The association between miR-122 levels and 28-day mortality in sepsis patients
All patients (n = 232) Odds ratios of miR-122 (95% CI) Unadjusteda 0.775 (0.703, 0.853) P < 0.001 Adjustedb 0.789 (0.713, 0.872) P < 0.001 Adjustedb + SOFA score Adjustedb + APACHE II score Adjusted + ARDS The predictive value of miR-122 AUC (95% CI) P-value Sensitivity Specificity
a b

RICU (n = 67)

SICU (n = 121)

EICU (n = 44)

0.776 (0.664, 0.908) P = 0.001 0.777 (0.663, 0.911) P = 0.002 0.781(0.665, 0.918) P = 0.003 0.709 (0.578, 0.870) P = 0.001 0.868 (0.647, 0.967) P = 0.023

0.77 (0.662, 0.894) P = 0.001 0.763 (0.655, 0.888) P < 0.001 0.791(0.677,0.925) P = 0.003 0.753 (0.639, 0.887) P = 0.001 0.721 (0.599, 0.867) P = 0.001

0.764 (0.610, 0.956) P = 0.019 0.650 (0.474, 0.891) P = 0.007 0.631 (0.448, 0.890) P = 0.009 0.622 (0.431, 0.897) P = 0.011 0.376 (0.133, 0.865) P = 0.034

0.772 (0.690, 0.863) P < 0.001 0.815 (0.734, 0.905) P < 0.001 0.812 (0.724, 0.911) P < 0.001

b

0.732 (0.665, 0.799) < 0.001 79.5% 63.5%

0.763 (0.65,0.877) < 0.001 75.9% 70.3%

0.706 (0.611,0.802) < 0.001 79.4% 60.7%

0.770 (0.574, 0.966) 0.009 80% 81.8%

Unadjusted by any value. Adjusted by age and gender. APACHE, Acute Physiology and Chronic Health Evaluation; ARDS, acute respiratory distress syndrome; AUC, are under the curve; EICU, Emergency Intensive Care Unit; RICU, Respiratory Intensive Care Unit; SICU, Surgery’s Intensive Care Unit; SOFA, Sequential Organ Failure Assessment.

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Abbreviations APACHE: Acute Physiology and Chronic Health Evaluation; ARDS: Acute respiratory distress syndrome; CRP: C-reactive protein; miRNA: microRNA; PCT: Procalcitonin; SOFA: Sequential Organ Failure Assessment. Competing interests The authors declare that they have no competing interests. Authors’ contributions HW and BY had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis and performed the experiments. They designed the study, analyzed data and wrote the manuscript. LX and YJ designed the studies, analyzed data and edited the manuscript. JD had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Acknowledgements This work is supported by the general program of the National Natural Science Foundation of China (81170008), and the general program of China’s 12th Five Year Plan and its military (CWS11J094). Author details 1 Department of Respiratory Medicine, Chinese PLA General Hospital, 28th Fuxing Road, Beijing 100853, PR China. 2Department of Respiratory and Critical Care Medicine, Beijing Chao-Yang Hospital, Beijing Institute of Respiratory Medicine, Capital Medical University, Beijing 100020, China. 3 International Medical Center, The General Hospital of Chinese People’s Liberation Army, Beijing 100853, China. 4Department of Respiratory Medicine, Beijing Nanyuan Hospital, Beijing 100076, China. 5Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA.

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doi:10.1186/s13054-014-0704-9 Cite this article as: Wang et al.: Serum miR-122 correlates with short-term mortality in sepsis patients. Critical Care 2014 18:704.